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 DNA Interpretation and why your DNA test doesn’t always seem accurate.

Have you received your 23andMe or other raw DNA data interpretation results and thought to yourself “Well - this doesn’t quite describe me?”

If you’ve taken an interest in direct to consumer genetics, then you likely have.

Here are the reasons why this happens:

All your genes combined are the instruction manual for the growth, maintenance, and function of your body. Each gene is a piece of information that codes for a working product.

Different variants (or variations - this is called genotype) of each gene can have different abilities in terms of well they work and/or when they work. This variability in genes is the major factor that explains the differences in traits between you, I, and other people (examples of traits are hair and eye color, height, body structure, susceptibility to disease, stress resistance, lifespan, creativity, problem-solving ability, etc.,).

Each trait is a group project involving the function of many genes.

Each of your traits is a cumulative result of the work of many genes. Simply put, each trait is a large group project. And, just like any group project, the final result is determined by the individual contribution of each gene involved.

Having one super-star member of a group does not necessarily guarantee the success of the project if the other members don’t show up or show up, but don’t contribute enough (or worse yet, don’t do any work AND sabotage the work of others - these variants are called “dominant negative”). For example, if a child’s genotype at “gene A” is associated with increased height, it does not guarantee that this child will grow up to be tall.  Ultimately, his/her height depends on the functionality of all the genes that contribute towards the “group project” that is vertical body growth, while also being dependent upon nutrition.

Predicting a trait based on a variant of a single gene must take into account the uncertainty due to the lack of knowledge of all the other genes (and their variants) in the group project that’s responsible for the trait. Therefore, trait prediction based on a single genotype reflects a probability range rather than a definite singular outcome. For the same reasons, individuals with the same genotype for a particular gene may not have the exact same trait as they may not have the same genotype for all the genes that determine this specific trait.

If the whole population is separated based on sex genotype, the average height of men will be higher than the average height of women.  That means that, a random man is likely to be taller than a randomly chosen woman. While the likelihood exists, it does not mean that every man is taller than every woman. In fact, there are many women who are taller than many men.

Conclusion: If a specific genotype is associated with a particular phenotype, it does not mean that each person with that genotype has that phenotype.

 

Whether specific genes contribute to the group project (trait) also depends on the environment.

The creation of this working product from a gene is called expression, or gene expression.

We do not express all the genes we have to their full capacity. By and large, our bodies mainly express those genes that are necessary for a specific environment. The different demands (or lack of such demands) imposed on our bodies by the environment is one of the reasons why an individual with a disease-associated genotype may not develop the disease.

Let’s imagine that a given gene variant makes a product that does not work as well.  Whether or not this genotype manifests in something bad (like a disease) depends on how much the body uses that product.

Think of it like this:  Functional differences between a 15-year old sedan and a brand new race car are not revealed in the stop-and-go city traffic, as either car is capable at moving at 15 mph speeds.  The functional differences are only revealed when these two cars are pushed to their max on the race track.  Similarly, certain mechanical problems in a car only reveal themselves when the car driven at highway speeds and would otherwise go undetected if the car is only used for city driving. In the same way, some genetic defects do not show up unless and until the genes are pushed “pedal to the metal” by the environment.

This means that if a person has a genotype that is associated with predisposition to type 2 diabetes (or another heritable disease), whether or not that person will actually develop diabetes it is largely influenced by the demands (stress) put on the individual’s body by his/her diet, lifestyle, and age.  Age, environment, and genetic predisposition to a disease together determine whether or not an individual develops the disease. 

Let’s imagine that a particular genetic variation is associated with increased height.  Whether or not this genetic predisposition results in a tall individual in part depends on the environment during his/her development. Does the environment stimulate or suppress that gene’s expression? Children born to US immigrants from Southeast Asia are significantly taller than their parents. This suggests that, although these people have the potential to be taller genetically, their nutrition limits full expression of growth genes.

Conclusion: While an individual’s specific genotype is their genetically encoded potential, the environment influences the physical manifestation of said potential.

 

The environment can impose long-term changes on genes’ contribution to a group project expression.

The environment can cause long-term changes in a gene’s expression. If genes are not expressed, their specific genotype does not matter. A blueprint of a product does not have an impact if the product is never built.

For example, an individual can have a functional genotype for gene Z, but if the gene is not allowed to express, the phenotype will be the same as in individuals with non-functional copies of gene Z. Once set, modifications that keep the gene from being expressed can last through the lifetime of an individual, and sometimes be passed onto that individual’s children and grandchildren.

In bees, queens and workers have very different behaviors, physiology, and morphology. A queen bee lives 4-7 years and can lay up to 2000 eggs per day; a worker bee is sterile and lives only a few weeks (summer) or months (winter). And yet these differences are NOT due to differences in their gene variants, but rather due to differences in expression of the genes. The master plan of which genes are permanently “shut down” and which are “turned on” is determined by the nutritional differences during larval development. Bee larvae fed exclusively with royal jelly develop into queens, while the ones fed by pollen and nectar develop into worker bees.  Genetically, any female bee larva has the potential to become either a queen bee or a worker bee.  However, the specific destiny is determined via selective gene expression, as determined by their food (environment) during development. Once this pattern is set, it cannot be undone; a worker bee cannot become the queen, no matter what food she eats.

Even genetically identical individuals (identical twins) can differ in certain traits due to age-associated epigenetic changes in gene expression.  Complex interactions of genes, environment, time and chance are the reason that genetically identical individuals differ in the way they look and what diseases they develop over time. These differences increase with age/time.

Take home message

An acorn holds the potential to become an oak, but how exactly this oak will look like is determined not only by its specific genetic variants but by the geographical location where it’s planted, weather, local soil and precipitation conditions, the presence of other plants, as well as damage caused by chance and accumulated over time.

Hence, when we interpret our DNA data analysis results we have to keep in mind that a trait can be the result of the interaction among many genes, the impact of each gene’s variants, and internal and external environment. Where genotype is the sheet music, the phenotype is the music.

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About the Authors:

Natalia Morsci, M.S., Ph.D., is a research scientist trained in genomics at the University of Missouri and in genetics and molecular biology at the University of Wisconsin. Her professional interests include genetic, cellular and systemic mechanisms of neuronal function and neurological dysfunction. 

Igor Rafalovich is a former neuroscientist with eight years of neuroscience research under his belt. As a researcher, he developed his passion for translating innovations in science and technology into solutions for restoring and enhancing cognitive health.

REFERENCES:

Adult height, nutrition, and population health. Nutrition Reviews. 2016 Mar; 74(3): 149–165.

A century of trends in adult human height. eLifeSciences. 2016;5:e13410

Nutrition and growth: assessing the impact of regional nutritional intake on childhood development and metacarpal parameters. Anatomy and Cell Biology. 2018 Mar;51(1):31-40.

The role of nutrition and genetics as key determinants of the positive height trend. Economics and Human Biology. 2014 Dec; Volume 15, 81-100.